We propose a concerted effort to understand the structure and regulation of mammalian genes and of their gene products using somatic cell genetic techniques combined with gene isolation methodologies. In particular we shall study primarily purine and pyrimidine synthesis in Chinese hamster ovary cells and mutants of these cells with alternations in these pathways. In addition, we shall carry out mammalian somatic cell biochemical genetic analysis of other pathways, such as inositol and metabolism, and shall attempt to expand these studies of human somatic cell mutants. In addition, we shall analyze nucleotide metabolism in human somatic cells taken from patients believed to have abnormalities in these pathways and in patients with selected progeriod syndromes. These analyses will include a study of the structures of genes and products producted by wild-type, mutant, and revertant cells and studies of the regulation, both genetic and metabolic, of these pathways. Genes will be isolated using DNA transfer and recombnant DNA procedures. Proteins will be purified and analyzed by classical biochemical methods and newer immunologic, electrophoretic and proteolytic methods developed in this laboratory. Genetic analysis will include dominance analysis and complementation analysis. Particular attention will be given to structural or functional relationships between genes such as linkage and between enzyme activities such as the existence of multifunctional polypeptides or multi-enzyme complexes.